Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
It has become increasingly apparent that various neurological assaults to the central nervous system (CNS) can result in long lasting disturbances and neuronal dysfunction. These include the induction of a state of neuroinflammation leading to cognitive impairment, apoptosis of immature oligodendrocytes, alterations in synaptic architecture and decreased neurogenesis amongst other events (Briner et al. (2010) Anesthesiolgy 112:546-556; Tan et al. (2009) Chin. Med J. (Engl) 122:455-459; Zhu et al. (2010) J. Cereb. Blood Flow Metabl 30.1017-1030; Sanders et al. (2009) Anesthesiology 110:1077-1085).
The neurological assaults include the use of conventional anesthetics to induce anesthesia and sedation, chronic pain, infection, development of neurodegenerative conditions such as Alzheimer's disease and brain hypoxia and asphyxia. These and other conditions lead to neuroinflammation which can result in a spectrum of neurological damage.
Hence, there is concern about the potential toxic side effects of currently used anesthetic and sedative drugs and the vulnerability of the CNS to neurodegenerative processes resulting from infection and disease development. The brain has innate protective mechanisms against toxic xenobiotic substances (Selye (1971) J Pharm Sci 60: 1-28). One such mechanism involves a nuclear receptor, steroid and xenobiotic receptor (SXR) which regulates expression of catabolic enzymes in response to steroid and xenobiotic compounds (see U.S. Pat. No. 6,911,537). SXR is also known as pregnane X receptor (PXR).
However, these innate protective mechanisms may be less efficient in the very young, elderly or subjects under stress such as following an acute illness, infection, chronic pain or surgery (Ek et al. (2010) Toxicol Lett 197:61-59). Brinton (US Publication No. 2010/0105646) has contemplated the use of hormonal neuroactive steroid molecules such as allopregnanolone for neuroprotection. However, these molecules were not contemplated for use in treating inflammation nor required PXR activation. The molecules exhibit hormonal properties and induce sedative effects.
There is a need to develop neuroprotection protocols for use in relieving, ameliorating, reducing or otherwise decreasing neuroinflammation and neuroinflammatory-promoting conditions such as neurological assault.